The broad and long term goal of this research project is to explore the roles of small conductance Ca2+- activated K (SK) channels in the mechanisms of ventricular arrhythmogenesis. We hypothesize that the SK current upregulation is an endogenous compensatory mechanism to protect the heart from arrhythmias related to reduced repolarization reserve, but under some conditions can result in excess repolarization reserve and proarrhythmic effects. The SK channel became a focus of our research after we discovered that the apamin- sensitive potassium current (IKAS, or SK current) is increased in both the rabbit and human ventricles with heart failure (HF). We also discovered that SK current is acutely increased in normal ventricles with hypokalemia, in a manner that depends on the ventricular activation sequence. These findings raise the intriguing possibility that SK current is a rescue current that compensates for the electrophysiological effects of increased intracellular Ca2+ load. While maintaining repolarization reserve in HF may be antiarrhythmic, we also found that excessive or heterogeneous shortening of the APD by SK current may be proarrhythmic. Our recent preliminary results indicate that IKAS is activated by isoproterenol, and that female rabbit ventricles express more SK current during early phase 2 than male ventricles. CyPPA activation of SK2 and SK3 causes ECG J point elevation, heterogeneous APD distribution, phase 2 reentry and spontaneous VF in normal rabbit ventricles. The latter finding suggests that SK current may also contribute to proarrhythmia in certain clinical conditions by creating excess repolarization reserve, such as in the J-wave syndromes. The incorporation of IKAS in computer models will generate important new insights into the dynamical effects of IKAS in ventricular repolarization. A combined mapping and computer simulation approach will be needed to fully understand the importance of IKAS in cardiac arrhythmogenesis, including both the proarrhythmic and antiarrhythmic potentials. We propose the following specific aims: Aim 1: Antiarrhythmic and proarrhythmic mechanisms of SK current in rabbit ventricles. The Aim 1A is designed to study the Purkinje cells (PCs) in both normal and failing rabbit ventricles to test the hypothesis that the SK current is increased in PCs and that blocking the SK current decreases the Ca2+-membrane potential coupling gain and promotes Ca2+ induced arrhythmias. The Aim 1B is designed to study SK current and J-wave syndrome. We hypothesize that (a) SK current is in part responsible for J-wave elevation and VF during hypothermia, and apamin reverses these proarrhythmic effects and (b) heterogeneous SK current activation can cause J wave elevation and spontaneous VF through heterogeneous shortening of APD and phase 2 reentry. Aim 2: Antiarrhythmic and proarrhythmic mechanisms of SK current in computer simulation. Aim 2A will systematically investigate the mechanisms of SK currents as a rescue mechanism preventing arrhythmias under QT prolongation and as a proarrhythmic mechanism under early repolarization. Aim 2B will extend and validate the hypotheses tested in the rabbits to human models.